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. 2022 Nov:168:110969.
doi: 10.1016/j.mehy.2022.110969. Epub 2022 Oct 27.

Proposal for the use of an inhalation drug containing 2-5 oligoadenylates for treatment of COVID-19

Gernot Bruchelt  1 , Jörn Treuner  2 , Karlheinz Schmidt  3
Affiliations

Proposal for the use of an inhalation drug containing 2-5 oligoadenylates for treatment of COVID-19

Gernot Bruchelt et al. Med Hypotheses. 2022 Nov.

Abstract

Interferons (IFN), first described 1957 by Isaacs and Lindemann, are antiviral proteins generated in cells after viral infections. One of several interferon-induced effector mechanisms is the so called 2-5A / RNaseL system: Interferon is produced in the virus-affected cells and released. After binding to cell membrane receptors of adjacent cells, 2-5 A synthetase (oligoadenylate synthetase, OAS) is generated, attaches to dsRNA section areas of the viral RNA and catalyses the production of 2-5 oligoadenylates from ATP. In 2-5 oligoadenylates, several adenosine residues (3-4 and more) are combined via phosphodiester binding in the unusual 2'-5' positions of the riboses. 2-5 oligoadenylates activate a RNaseL which degrades the viral RNA. Recently, characteristic gene mutations and other disturbances concerning the interferon system were detected in patients with severe COVID-19, leading to problems of 2-5 oligoadenylate synthesis and the activation of RNAseL. In order to circumvent these problems, we hypothesize that a direct application of 2-5 oligoadenylates, included in an inhalation spray, may be effective in treatment of severe COVID-19 infections of the respiratory system. In contrast to some other anti-COVID-19 drugs, oligoadenylates act inside the cells (like e.g. Paxlovid) and are therefore independent of cell surface mutations of the virus. For confirmation of our hypothesis, proof of concept investigations in vitro are suggested, before a possible clinical application can be considered.

Keywords: 2-5 Oligoadenylates; 2-5A/RNaseL system; COVID-19; Interferon; SARS-CoV-2.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
The Interferon-induced 2-5A / RNaseL system.
Fig. 2
Fig. 2
Structure and formation of 2-5 oligoadenylates from ATP by the 2-5A synthetase. Shown is the dimeric form which was generated by connection of ATP with AMP (after splitting of PP from the second ATP molecule) in 2‘-5‘position of the ribose(s).
Fig. 3
Fig. 3
Preferred degradation of viral RNA by activated RNaseL according to the model of Nilsen and Baglioni .
Fig. 4
Fig. 4
Proposed experiments for evaluation of our hypothesis to use 2-5 oligoadenylates for treatment of severe COVID-19. More detailed information: see text.
See this image and copyright information in PMC

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